Use of Aalkylphophocholines in Combination with Antitumor Medication for the Treatment of Benign and Melignant Oncoses in Humans and Mammals

ABSTRACT

The invention relates to the use of alkylphosphocholines in combination with antimetabolite antitumor substances for the treatment of benign and malignant oncoses in humans and animals. It is possible in this connection for the alkylphosphocholines to be employed in a combination according to the invention with one or more antimetabolite antitumor substances. Preferred alkylphosphocholines are described by the Formula II. 
     
       
         
         
             
             
         
       
     
     One such preferred alkylphosphocholine is perifosine.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/632,187, filed on Jul. 30, 2003, which claims the benefit of U.S.Provisional Application No. 60/399,615, filed Jul. 30, 2002, which ishereby incorporated by reference.

BACKGROUND OF THE INVENTION

Alkylphosphocholines are a new class of organic compounds, which exhibitdiversified anti-neoplastic activities (M. Lohmeyer and R. Bittman,Antitumor Ether Lipids and Alkylphosphocholines, DOF, 19 (11), 1021-1037 (1994)). The effect of the alkylphosphocholines in this connection maybe based on different, molecular and biochemical mechanisms, some ofwhich take place on the level of the plasma membrane of the cell.

It is well known that alkylphosphocholines influence inositolmetabolism, the interaction with phospholipases or inhibition of proteinkinase C and thus that this class of substances has a general influenceon cellular signal transduction (K. Maly et al., Interference of NewAlkylphospholipid Analogues With Mitogenic Signal Transduction,Anti-Cancer Drug Design, 10, 411-425 (1995); and P. Hilgard, et al.,D21266, A New Heterocyclic Alkylphospholipid with Antitumor Activity,Eur. J. Cancer, 33 (3), 442-446 (1997)). Thus, the alkylphosphocholineperifosine shows growth-inhibitory properties in relation to variousmelanoma, CNS, lung, colon, prostate and breast cancer cell lines withan IC₅₀ ranging from 0.2 to 20 μM.

It is further known that perifosine blocks tumor cells in the G₁-S andG2-M phase of the cell cycle (V. Patel, et al., A NovelAlkylphospholipid, Induces p. 21 ^(Walf) Expression in SquamousCarcinoma Cells through a p53-independent Pathway, Leading to Loss inCyclin dependent Kinase Activity and Cell Cycle Arrest, Cancer Research62, 1401-1409 (2002)).

It is known that the use of alkylphosphocholines before or together withradiation therapy leads its synergistic effects during the treatment oftumors (P. Principe et al., Evaluation of Combinations of AntineoplasticEther Phospholipids and Chemotherapeutic Drugs, Anti-Cancer Drugs, 3(6), 577-587 (1992)). It has also been reported that differentglycerol-3-phospholipids, such as ET-18-OOCH₃, in combination withdifferent DNA-interacting substances or tubulin binders increase theanti-tumor activity in vitro in a different tumor cell lines (P.Principe et al., Synergistic Cytotoxic Effect of Aza-alkylphospholipidsin Association with Chemotherapeutic Drugs, J. Lipid Mediators CellSignalling, 10 (1-2), 171-173 (1994)).

BRIEF SUMMARY OF THE INVENTION

Surprisingly, it was now possible to show that linearalkylphosphocholines of the general Formulas I and II are suitable foruse in a combination according to the invention with other drug productsfor the treatment of benign and malignant oncoses in humans and mammals.

In this connection, the present invention relates to the novel use ofalkylphosphocholine in combination with antitumor medications forart-recognized therapeutic activities attributed to the treatment ofbenign and malignant oncoses in humans and mammals.

It is therefore an object of this invention to provide a novel means oftreating tumors with an inventive combination of linearalkylphosphocholines and anti-tumor substances.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel use of linearalkylphosphocholines of the general Formulas I and II in an inventivecombination with other medicinal drugs for the treatment of benign andmalignant oncoses in humans and mammals. According to one aspect of theinvention, the compounds of the general Formulas I and II can be used inan inventive combination with anti-tumor substances. Anti-tumorsubstances may be alkylating agents, anti-metabolites, plant alkaloids,platinum compounds, tumor antibiotics and agonists or antagonists ofnatural hormones. The anti-tumor substances may be selected from, butare not restricted to cis-platinum, carboplatinum, oxaliplatinum,bleomycin, doxorubicin, methotrexate, paclitaxel, docetaxel,vincristine, vinblastine, etoposide, teniposide, ifosfamide,cyclophosphamide, 5-fluorouracil, fludarabin, gemcitabine andcytarabine.

It is moreover possible for the alkylphosphocholines of the generalFormula I and II to be employed in a claimed combination with inhibitorsof signal transduction in the form of high and low molecular weightinhibitors of receptor and/or cytosolic kinases. These inhibitors may beselected from but not restricted to monoclonal antibodies andheterocyclic compounds.

The alkylphosphocholines of the general Formulas I and II, on which theinvention is based, may be used in the form of finished medicinal drugs.

The compounds, on which the invention is based, are described by thegeneral Formulas I and II:

in which, independently of one another,

-   n, m, p, z is a whole number between 0 and 4,-   is O, S, NH;-   R is hydrogen, a linear or branched C₁ to C₂₀ alkyl group, which may    be saturated or unsaturated with one to three double and/or triple    bonds and unsubstituted or optionally substituted at the same or at    different carbon atoms with one, two or more halogen, nitro, cyano,    hydroxy, C₁ to C₆ alkoxy, amino, mono-(C₁ to C₄) alkylamino or    di-(C₁ to C₄) alkylamino groups,-   R₁, R₂, R₃ independently of one another represent hydrogen, a linear    or branched (C₁ to C₆) alkyl group, preferably methyl and ethyl, a    (C₃ to CO cyclo alkyl group, which may be unsubstituted or    optionally substituted at the same or different carbon atoms with    one, two or more halogen, nitro, cyano, hydroxy, C₁ to C₆ alkoxy,    amino, mono-(C₁ to C₄) alkylamino or di-(C₁ to C₄) alkylamino    groups.

According to a further aspect of the invention, a method for controllingtumors in humans and in mammals is provided and comprises administeringat least one of the compounds of the general Formula I and II on whichthe invention is based to the human or a mammal in an amount effectivefor tumor treatment before or during a treatment with approved antitumorsubstances.

The therapeutically effective dose, to be administered for thetreatment, of the particular compound of the general formula I and II onwhich the invention is based depends inter alia on the nature and thestage of the oncosis, the age and sex of the patient, the mode ofadministration and the duration of treatment.

The compounds on which the invention are based can be administered in adrug product as liquid, semisolid and solid drug forms. This takes placein the manner suitable in each case in the form of aerosols, oralpowders, dusting powders and epipastics, uncoated tablets, coatedtablets, emulsions, foams, solutions, suspensions, gels, ointments,pastes, pills, pastilles, capsules or suppositories.

Examples Example 1 Administration of Perifosine (D-21266) in Combinationwith Cisplatin

-   In vivo Experiment: DMBA-induced rat mammary carcinoma model-   Experimental Animal: Sprague-Dawley rat, female-   Procedure: The mammary carcinoma was induced by a single oral dose    of DMBA. The animals received perifosine from day 0 to day 14 and    were observed up to day 42. The weight of the tumor mass was    estimated by palpation and comparison with plastic models. The    initial weight is set equal to 100%.-   Administration: Perifosin 14×6.81 mg/kg p.o.-   Cis-platinum 4×1 mg/kg i.p.-   Effect: Reduction in the tumor was distinctly greater and longer    through the combination treatment than through the single treatment    in each case.

TABLE 1 Tumor Starting Day 21, Change p Test vs. Treatment Weight (g) in% Control Control 1.0 875 — Perifosin (D-21266) 0.9 −25 <0.001Cis-platinum 0.9 410 0.120 Perifosin (D-21266) + 0.8 −75 <0.001Cis-platinum

Example 2 Administration of Perifosine in Combination withCyclophosphamide

-   In vivo Experiment: DMBA-induced rat mammary carcinoma model-   Experimental Animal: Sprague-Dawley rat, female-   Procedure: The mammary carcinoma was induced by a single oral dose    of DMBA. The animals received perifosine from day 0 to day 14 and    were observed up to day 42. The weight of the tumor mass was    estimated by palpation and comparison with plastic models. The    initial weight is set equal to 100%.-   Administration: Perifosine 14×6.81 mg/kg p.o.    -   Cyclophosphamide 100 mg/kg, VZ 0, i.v.-   Effect: Reduction in the tumor was distinctly greater and longer    through the combination treatment than through the single treatment    in each case.

TABLE 2 Tumor Starting Day 21, Change p Test vs. Treatment Weight (g) in% Control Control 1.0 875 — Perifosin (D-21266) 0.9 −25 <0.001Cyclophosphamide 0.9 500 0.011 Perifosin (D-21266) + 0.8 −83.3 <0.001Cyclophosphamide

Example 3 Administration of Perifosine in Combination with Adriamycin

-   In vivo Experiment: DMBA-induced rat mammary carcinoma model-   Experimental Animal: Sprague-Dawley rat, female-   Procedure: The mammary carcinoma was induced by a single oral dose    of DMBA. The animals received perifosine from day 0 to day 14 and    were observed up to day 42. The eight of the tumor was mass was    estimated by palpation and comparison with plastic models. The    initial weight is set equal to 100%.-   Administration: Perifosine 14×6.81 mg/kg p.o.    -   Adriamycin 4×2.15 mg/kg i.p.-   Effect: Reduction in the tumor was distinctly greater and longer    through the combination treatment than through the single treatment    in each case.

TABLE 3 Tumor Starting Day 21, Change p Test vs. Treatment Weight (g) in% Control Control 1.0 875 — Perifosin (D-21266) 0.9 −25 <0.001Adriamycin 1.0 781 0.197 Perifosin (D-21266) + 1.9 −70 <0.001 Adriamycin

In the manner described above, the present invention thus provides amethod for the use of alkylphosphocholines in combination with antitumormedications for the treatment of benign and malignant oncoses in humansand mammals. While this invention has been described with reference tothe preferred embodiments, these are illustrative only and not limiting,having been presented by way of example. Other modifications will becomeapparent to those skilled in the art by study of the specification anddrawings. It is thus intended that the following appended claims includesuch modifications as fall within the spirit and scope of the presentinvention.

1. A method of treating benign and malignant oncoses, wherein the methodcomprises administering a therapeutically effective amount of analkylphosphocholine compound of the general Formula I or II:

in which, independently of one another: m, n, p, z are a whole numberbetween 0 and 4; X is O, S, NH; R is hydrogen, a linear or branched C₁to C₂₀ alkyl group, which may be saturated or unsaturated with one tothree double and/or triple bonds and unsubstituted or optionallysubstituted at the same or at different carbon atoms with one, two ormore halogen, nitro, cyano, hydroxy, C₁ to C₆ alkoxy, amino, mono-(C₁ toC₄)-alkylamino or di-(C₁ to C₄)-alkylamino groups; R₁, R₂, R₃independently of one another represent hydrogen, a linear or branched(C₁ to C₆) alkyl group, preferably methyl and ethyl, a (C₃ to C₇)cycloalkyl group, which may be unsubstituted or optionally substitutedat the same or different carbon atoms with one, two or more halogen,nitro, cyano, hydroxy, (C₁ to C₆) alkoxy, amino, mono-(C₁ to C₄)alkylamino or di-(C₁ to C₄) alkylamino groups and pharmaceuticallyacceptable salts and prodrugs thereof, wherein said alkylphosphocholineis administered before and/or during treatment with at least oneantimetabolite.
 2. A method of treating benign and malignant oncoses,wherein the method comprises administering a therapeutically effectiveamount of an alkylphosphocholine compound having the structure ofFormula I:

in which, independently of one another: m, n are a whole number between0 and 4; X is O; R is H or a straight-chain or branched (C₁-C₁₇)-alkylgroup which may be saturated or unsaturated with one to three doubleand/or triple bonds; R₁, R₂, R₃ are, independently of one another, H ora straight-chain or branched (C₁-C₆)-alkyl group, preferably methyl andethyl, a (C₃-C₇)-cycloalkyl group, wherein said alkylphosphocholine isadministered before and/or during treatment with at least oneantimetabolite.
 3. A method of treating benign and malignant oncoses,wherein the method comprises administering a therapeutically effectiveamount of an alkylphosphocholine compound having the structure ofFormula II:

in which, independently of one another: m, n, p, z are a whole numberbetween 0 and 4; X is O; R is H, a straight-chain or branched(C₁-C₁₇)-alkyl group which may be saturated or unsaturated with one ortwo double and/or triple bonds; R₁, R₂ are, independently of oneanother, H or a straight-chain or branched (C₁-C₆)-alkyl group,preferably methyl and ethyl, a (C₃-C₇)-cycloalkyl group, wherein saidalkylphosphocholine is administered before and/or during treatment withat least one antimetabolite.
 4. The method according to claim 1 whereinsaid alkylphosphocholine is octadecyl 1,1-dimethylpiperidinium-4-ylphosphate (perifosine).
 5. The method according to claim 1 wherein saidantimetabolite is selected from the group consisting of 5-fluorouracyl,cytarabine, gemcitabine.
 6. The method according to claim 1 wherein saidantimetabolite is 5-fluorouracyl.
 7. The method according to claim 1wherein said antimetabolite is cytarabine.
 8. The method according toclaim 1 wherein said antimetabolite is gemcitabine.
 9. The methodaccording to claim 1 wherein said alkylphosphocholine is octadecyl1,1-dimethylpiperidinium-4-yl phosphate and wherein said antimetaboliteis selected from the group consisting of 5-fluorouracyl, cytarabine, andgemcitabine.
 10. The method according to claim 9 wherein saidantimetabolite is 5-fluorouracyl.
 11. The method according to claim 9wherein said antimetabolite is cytarabine.
 12. The method according toclaim 9 wherein said antimetabolite is gemcitabine.
 13. The methodaccording to claims 1, wherein said alkylphosphocholine is administeredbefore and/or during treatment with two or more antimetabolites.
 14. Themethod according to claim 9, wherein said alkylphosphocholine isadministered before and/or during treatment with two or moreantimetabolites.